Anaesthetic implications of chemotherapy

Key points
Chemotherapy causes damage to healthy cells leading to side-effects affecting
the respiratory, cardiovascular, renal, hepatic, nervous, gastrointestinal (GI), and
haematopoietic systems.

After completion of chemotherapy treatment, some toxic effects must be

considered to be long term (e.g. bleomycin and anthracyclines).

The chemotherapy agent bleomycin can cause severe pulmonary fibrosis

potentially aggravated by the administration of high concentration oxygen.

The myocardial depressant effect of anaesthetic agents can exacerbate the

cardiotoxic side-effects after chemotherapy.

Careful preoperative assessment is essential to identify toxicity and avoid

potential complications.

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Chemotherapy, radiotherapy, and surgery are the most common modalities used
to treat a patient with cancer. Many established chemotherapy drugs are antiproliferative agents, targeting rapidly dividing cancer cells but also damaging
non-malignant dividing cells, leading to toxicity. Chemotherapy usually causes
cell death via a drugreceptor interaction that stimulates a cascade of
catastrophic events, usually resulting in apoptosis. Common toxicities include
cardiac, pulmonary, renal, hepatic, GI, bone marrow, and neurological damage.
Table 1 lists the common anticancer action of the frequently used chemotherapy
drugs. Newer anticancer agents target other differences between cancer cells
and normal cells in order to exert a differential effect but all still have significant
toxicity. This article will focus on the challenges that cancer patients receiving
chemotherapy present to the anaesthetist.

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Table 1
Mechanism of action of chemotherapy drug groups and example drugs for each
group

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Timing of chemotherapy and surgery

Chemotherapy has a role in several different clinical settings in the treatment of

cancer, which can be broadly classified as:

neoadjuvant therapy before definitive surgical resection of the primary tumour,

metastases, or both. The aims are variable depending on tumour type, aiming to
improve the chance of complete resection and survival, or reducing the need for
more complex or disfiguring surgery, for example, lumpectomy rather than
mastectomy in breast cancer treatment.

adjuvant therapy after tumour resection, aiming to reduce the risk of tumour
recurrence.

palliative therapy to improve quality of life and prolong survival without the
possibility of cure.

Combination chemotherapy is frequently administered to increase cancer cell kill

and reduce drug resistance. Drugs chosen may have different mechanisms of
action, leading to synergistic effects. Chemotherapy is administered in cycles,
usually given every 23 weeks, usually over a 36 month period (but sometimes
significantly longer) with recovery phases between each cycle to allow repair of
normal tissues and resolution of toxic effects. The use of multidosing regimes will
also increase the likelihood of cancer cell death, as when a single dose is
administered not all of the cells will be in the susceptible part of the cell cycle.

Patients may therefore present for both elective and emergency surgery after
administration of chemotherapy. Table 2 shows a list of common elective
procedures performed in cancer patients. In the emergency situation, surgery
may be unrelated to ongoing cancer management and may occur during a
course of chemotherapy. As a consequence, all anaesthetists should be aware of
the potential complications presented by chemotherapy drugs and have an
appropriate management plan for their patients.

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Table 2

Common elective operations in cancer patients that may follow chemotherapy

administration

As part of preoperative assessment, the anaesthetist should take a focused

history of cancer management. A detailed drug history includes the precise
chemotherapy regime used and any specific toxic effects suffered by the patient.
Clinical features of toxicity which may alert the anaesthetist to more serious
systemic complications include shortness of breath, palpitations, chest pains,
and fever. A thorough examination may also reveal signs that require further
investigation before surgery. Routine investigations performed such as full blood
counts, blood biochemistry, and an ECG are important in management of the
cancer patient before theatre. Other investigations, for example, a chest X-ray,
an arterial blood gas, pulmonary function tests, and an echocardiogram, may be
required depending upon the treatment regimen used.

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A systems approach to toxicity after chemotherapy

The toxic effects of most of the commonly used chemotherapy drugs are well
established (Table 3). Some occur acutely, for example, hypersensitivity
reactions, or in the short-term, for example, myelosuppression and renal or
hepatic impairment, whereas some need to be considered as long-term
problems, for example, bleomycin pulmonary toxicity and chemotherapy-related
cardiovascular complications.

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Table 3
Systems-based chemotherapy toxicities and commonly associated
chemotherapy drugs. GM-CSF, granulocyte macrophage colony-stimulating
factor; BCG, Bacillus CalmetteGuerin

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Respiratory system

Patients receiving chemotherapy who present with respiratory symptoms and

signs present a diagnostic challenge: infection, metastatic disease, pulmonary

embolism, or drug-induced pulmonary toxicity are possible diagnosis in the

cancer patient. Drugs such as bleomycin, cyclophosphamide, nitrosureas,
mitomycin, busulphan, and methotrexate commonly cause pulmonary toxicity
but many other drugs may also have an association (Table 3).

Initial presentation can be subtle; the patient may be asymptomatic with no loss
of physiological function or may complain of a dry cough or increasing
breathlessness with exercise. There may be minimal changes on chest X-ray and
no marker lesions. The pathogenesis of pulmonary toxicity secondary to
chemotherapy is often uncertain. Methotrexate and cyclophosphamide classically
cause pneumonitis. Treatment is often unsuccessful and progressive pulmonary
fibrosis may ensue.1

Due to the immunosuppressant effects of chemotherapy drugs (most

chemotherapy agents cause myelosuppression including neutropenia), patients
may present acutely unwell with infections such as pneumonia. Postoperatively,
these patients may require a period of artificial ventilation.

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Bleomycin

Bleomycin is a particularly important chemotherapy drug for the anaesthetist to

be aware of. Bleomycin is often used to treat germ cell tumours and Hodgkin's
disease in a curative setting. The major limitation of bleomycin therapy is the
potential for subacute pulmonary damage that can progress to life-threatening
pulmonary fibrosis. Pulmonary toxicity occurs in 610% patients and can be
fatal.2 Exposure to high-inspired concentration oxygen therapy, even for short
periods, as experienced during anaesthesia, is often implicated in causing rapidly
progressive pulmonary toxicity in patients previously treated with bleomycin.3
These claims have been considered controversial by some, but it is the authors'
recommendation that any patient previously exposed to bleomycin therapy
should be treated as high risk, and summary guidance regarding oxygen therapy
is shown in Table 4.

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Table 4
Authors' guidance for oxygen therapy in patients who have received
bleomycin10

Bleomycin-induced lung injury typically occurs insidiously during the first 6

months after starting treatment, but the potential for high-inspired fractions of
oxygen to provoke pulmonary toxicity remains a life-long risk. All patients who
have ever received bleomycin should wear an alert card and an alert sticker
should be placed on their notes.

The symptoms of bleomycin-induced pulmonary toxicity are non-specific and

include dry cough and breathlessness. Patients may also experience pleuritic
chest pain and fever. On examination, pulmonary crackles and hypoxaemia may
be found. The diagnosis of bleomycin toxicity must be considered in all
respiratory illnesses in patients who have ever received bleomycin.

Bleomycin toxicity has typical appearances radiologically:

Linear interstitial shadowing may be seen, which can look similar to Kerly B lines
seen in pulmonary oedema.

Confluent airspace shadowing may be present, which may be diagnosed as

infection if the diagnosis of bleomycin lung injury is not considered.

Pneumothorax and pneumomediastinum are recognized complications in severe

bleomycin lung injury.

There are particular concerns for patients who are undergoing surgery and who
have been treated with bleomycin. Oxygen therapy can both induce and
exacerbate bleomycin lung injury. A high concentration of inspired oxygen
increases the risk of developing bleomycin-induced lung injury and a lower
inspired oxygen concentration reduces the risk. When bleomycin has been
administered preoperatively, reduced oxygen concentrations should be used
during anaesthesia and postoperatively.3

Pre-assessment of a patient with previous bleomycin exposure will require a

thorough history and examination. Depending upon clinical findings,
investigations required may include a chest X-ray, arterial blood gases, lung
computed tomography, pulmonary function tests, and bronchoscopy. Oxygen
should be prescribed on the drug chart, and the dose of oxygen adjusted
frequently to maintain the minimum exposure to achieve a target range of
peripheral oxygen saturation between 88% and 92%. If oxygen saturations are
higher than this, then oxygen should be stopped or the dose reduced. Ventilatory
strategies involving the use of PEEP and careful fluid balance will limit the
amount of oxygen required.

Postoperatively, chest physiotherapy, good analgesic regimes, and early

mobilization also minimize the requirement for oxygen.

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Cardiovascular system

Cardiac toxicity secondary to chemotherapy is common and may be life

threatening, cause significant morbidities, or necessitate a change in treatment.
The pathologies encountered include hypotension, hypertension, arrhythmias,
myocardial infarction, congestive cardiac failure, cardiomyopathy, myocarditis,
and pericarditis, leading to pericardial effusion and cardiac tamponade. Cardiac
toxicity can be immediate or delayed, after completion of the course of
chemotherapy.

Numerous chemotherapy drugs cause Torsades de Pointes, including cisplatin

and anthracyclines (including epirubicin and doxorubicin). This results from QT
prolongation and may terminate spontaneously, or may lead to ventricular
tachycardia and possibly death. Management would be as for any other cause of
the arrhythmia. The anthracyclines are the most common drugs implicated in
cardiac toxicity, but other drugs such as cyclophosphamide, 5-fluorouracil (5-FU),
bleomycin, paclitaxel, and docetaxel can also cause serious cardiac toxicity.
There are lots of gaps in the data regarding cardiac toxicity and chemotherapy
drugs. Most data are in the form of case series. Chemotherapy drugs tend to
damage myocytes, and as there is very little mitosis beyond early adulthood, the
heart has to functionally adapt to change, for example, ejection fraction may be
preserved but there is decreased cardiac reserve. Radiotherapy may be used
alongside chemotherapy and it may cause damage to cardiac valves, vessels,
and the pericardium.4

The mechanism by which anthracyclines cause cardiac damage is multifactorial

but includes production of free radicals leading to apoptosis of myocytes and,
subsequently, acute and irreversible cardiac damage. Damage can be severe
and life threatening. Clinical signs, however, are late, usually after 12 months or
more, by which time it is too late to alter management. Cardiology opinion
should be considered as angiotensin-converting enzyme inhibitors can be used to
improve ejection fraction.

Cyclophosphamide causes direct endothelial damage and haemorrhagic

pericarditis or myocarditis. 5-FU was previously thought to cause acute coronary
spasm, but recent evidence suggests that this drug too probably causes myocyte

toxicity, which is unpredictable in nature except for an increased frequency in

patients with a history of ischaemic heart disease.

Risk factors for cardiotoxicity include pre-existing cardiac disease, the use of
concurrent chemotherapy agents, age over 70 yr, female gender, and current or
previous radiation therapy involving the mediastinum.5 New evidence also shows
that at 30 yr after chemotherapy administration, there is an eight- to nine-fold
additional mortality from cardiovascular disease in childhood cancer groups.6
Dexrazoxane has been used as a cardioprotective agent but is associated with an
increased incidence of secondary malignancies.

When assessing a patient for theatre who has received chemotherapy, the
anaesthetist should be mindful of the potential cardiac complications. A focused
history and examination, looking specifically for signs and symptoms or cardiac
dysfunction, should be obtained. Apart from the routine perioperative
investigations, an ECG and a 2D echocardiogram should be requested. The
echocardiogram should focus on specific details regarding cardiac wall
contractility, left ventricular ejection fraction, and pericardial fluid. If necessary,
the patient should be referred for cardiology review for optimization before
surgery.

The anaesthetic plan intraoperatively will depend upon preoperative findings.

The myocardial depressant effect of the commonly used anaesthetic agents may
be compounded by the previous exposure to chemotherapy agents, even in
patients with apparently normal cardiac function. As a consequence, all these
patients should be treated as high risk for potential cardiac events during
anaesthesia. Invasive arterial pressure and cardiac output monitoring will often
be necessary to maintain normal physiological parameters. ECG alarm limits
should be carefully selected to alert the anaesthetist to any changes in electrical
activity within the heart. Normothermia should be maintained using forced air
warming devices and warmed fluids. This care should be maintained into the
postoperative phase, when careful monitoring in a high dependency unit may be
necessary.

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Renal system

Several chemotherapy drugs are nephrotoxic, causing either acute or chronic

renal failure (Table 3). The platinum-based chemotherapy agents cisplatin,
carboplatin, and oxaliplatin, used to treat a huge number of cancers including
the lung, upper and lower GI, ovarian, and germ cell tumours, are a common
cause of renal tubular and glomerular damage, which can be treatment-limiting.

Subsequently, these patients have a long-term higher incidence of hypertension

leading to cardiovascular pathology. Ifosfamide can cause a proximal tubular
abnormality, cyclophosphamide can cause haemorrhagic cystitis, and mitomycin
C is associated with a syndrome encompassing microangiopathic haemolytic
anaemia and renal failure.7

Of particular importance to the anaesthetist is the knowledge that the

nephrotoxic process is compounded by dehydration and concurrent use of nonsteroidal anti-inflammatory drugs. Careful fluid optimization and analgesic
prescribing is imperative in the perioperative phase.

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Nervous system

Chemotherapy may damage any part of the human nervous system. The most
common agents with neurotoxic side-effects of significance to the anaesthetist
are vincristine and cisplatin.

The vinca alkaloid vincristine can cause severe neurotoxicity. It may be used to
treat lymphoma and leukaemia. Vincristine can cause peripheral neuropathy,
muscle pain, cranial neuropathy, and seizures. Of particular concern to the
anaesthetist are the effects on the autonomic nervous system, with the
development of orthostatic hypotension, and the rare but serious condition of
vocal cord palsy.8 Vincristine may also exacerbate pre-existing neurological
conditions. High-dose methotrexate is used to treat, among other cancers, bone
sarcomas and may induce acute encephalopathy, encompassing confusion,
seizures, hemiparesis, and coma (usually reversible). Ifosfamide also classically
causes encephalopathy, especially in female patients with large pelvic tumours.
Paclitaxel and oxaliplatin commonly cause peripheral neuropathy.

Preoperatively, a full neurological examination should be conducted and

documented to detect any neurological damage. Regional anaesthesia is
relatively contraindicated in any patient demonstrating neurological side-effects
after chemotherapy treatment, and, if attempted, careful documentation of
deficit before anaesthesia is pertinent.

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Gastrointestinal system

Gastrointestinal toxicity is common after administration of most chemotherapy

drugs and includes nausea and vomiting, mucositis, and diarrhoea. Not
surprisingly, dehydration may occur. In these cases, fluid and electrolyte
resuscitation before surgery will be indicated, and rapid sequence induction of
anaesthesia to prevent aspiration should be considered.

Direct trauma as a consequence of laryngoscopy will exacerbate the mucositis

caused by chemotherapy and can cause severe bleeding leading to difficult
visualization of the airway.

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Hepatic system

Abnormal liver function tests are a common problem in the cancer patient with
possible causes including hepatic metastases, infections, liver disease (e.g.
alcoholic liver disease), and hepatotoxic medications. Chemotherapy-related liver
damage can also occur, including parenchymal damage with fatty change,
cholestasis, and hepatocellular necrosis (Table 3). Methotrexate is known to
cause hepatic cirrhosis and fibrosis. Diffuse hepatocellular destruction has been
seen secondary to cyclophosphamide treatment.9 Many chemotherapy drugs are
metabolized by the liver and, as such, require dose reductions if liver function is
impaired. Usual precautions for anaesthetic drug dosing in patients with hepatic
disease should be applied, and regional anaesthesia may be contraindicated as a
consequence of the associated coagulopathy.

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Haematopoietic system

Most chemotherapy drugs affect bone marrow and the peripheral blood cells
leading to myelosuppression. Life-threatening sepsis and rapid deterioration can
occur if a patient develops an infection while neutropenic. Symptoms and signs
may not be typical and fever may be absent. Appropriate broad-spectrum
antibiotics must be administered immediately, according to local policy.
Pancytopenia can have serious implications for anaesthesia and surgery, causing
a reduced oxygen-carrying capacity, an increased risk of haemorrhage and
opportunistic infection. A thorough assessment of bone marrow function is
imperative before anaesthesia. Consultation with a senior haematologist should
be considered. Myelosuppression is usually partially or completely reversible

within 6 weeks of cessation of chemotherapy, but in some patients, it may be

longer term.

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Conclusion

Chemotherapy drugs can produce serious multisystemic side-effects, which

directly impinge on the patient's perioperative care. It is the anaesthetist's
responsibility to be aware of these potential complications. A thorough
preoperative assessment and structured intraoperative and postoperative
management plan is required for all patients with a history of previous exposure
to chemotherapy agents.

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Declaration of interest

None declared.

The Author [2011]. Published by Oxford University Press on behalf of the

British Journal of Anaesthesia. All rights reserved. For Permissions, please email:
journals.permissions@oup.com
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